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Goltz Syndrome

Main Features

X-linked dominant multisystem ecto-mesodermal dysplasia affecting skin, skeleton, eyes, teeth, and face; ~90% of patients are female (M:F ~1:9), with hemizygous variants usually lethal in utero

  • Blaschkolinear dermal hypoplasia (atrophic, erythematous, or translucent streaks) present at birth, often with congenital patchy skin aplasia (aplasia cutis)
  • Soft yellow-pink nodular fat herniation into the dermis (60-70%) and telangiectasias (~80%)
  • Blaschkolinear hyper- and hypopigmentation
  • Periorificial and mucosal papillomas (perinasal, perioral, perianal, genital, laryngeal, esophageal) developing after infancy; may cause dysphagia or airway obstruction
  • Ridged or dystrophic nails, micronychia; sparse brittle hair, patchy alopecia
  • Limb malformations in >50%: ectrodactyly (“lobster claw”), oligodactyly, syndactyly, polydactyly, split hand/foot, transverse and long-bone reduction defects
  • Osteopathia striata on long-bone metaphyseal radiographs: asymptomatic, but a useful diagnostic clue in mild cases
  • Proposed clinical criteria: at least 3 characteristic skin findings (patchy skin aplasia, nodular fat herniation, Blaschkolinear pigmentary change, telangiectasia, ridged dysplastic nails) plus at least 1 characteristic limb malformation

Eye Findings

Ocular anomalies in ~15% (older series 20-40%), typically asymmetric, ranging from cosmetic to blinding

  • Microphthalmia (most common) and anophthalmia
  • Iris and chorioretinal coloboma; retinal and optic nerve dysplasia
  • Lacrimal and nasolacrimal duct abnormalities
  • Strabismus, cataract, corneal and anterior chamber defects
  • Eyelid and conjunctival papillomas, ectropion, ptosis, sparse eyelashes and eyebrows

Other Findings

  • Craniofacial: pointed chin, facial asymmetry, midface/maxillary hypoplasia, notched alae nasi, small or protruding ears, thin notched upper lip
  • Dental (20-50%): enamel hypoplasia, vertical grooving, hypodontia/oligodontia, irregular crowns, delayed eruption, malocclusion
  • Ears and hearing: microtia, aural atresia, conductive and sensorineural hearing loss, vestibulocochlear dysplasia
  • Central nervous system: intelligence usually normal, but intellectual disability, speech delay, microcephaly, and structural brain anomalies occur
  • Growth: short stature and growth failure; growth hormone deficiency investigated as a contributor
  • Renal: fused or duplex kidney, renal hypoplasia, cysts
  • Gastrointestinal and abdominal wall: omphalocele, midline thoracoabdominal wall defects (overlap with pentalogy of Cantrell and limb-body wall complex)
  • Rare: giant cell tumor of bone, supernumerary nipple, athelia
  • Histopathology: atrophic dermis with adipocytes abutting the epidermis or clustered in reticular dermis, dilated papillary dermal vessels, sparse disorganized collagen</em>

Etiology

  • X-linked dominant inheritance; ~95% of cases in females are de novo, ~5% inherited
    • Loss-of-function pathogenic variants in PORCN (Xp11.23), encoding porcupine O-acyltransferase, which palmitoylates Wnt proteins for secretion; disrupted Wnt/beta-catenin signaling impairs ecto-mesodermal development
  • Male survivors result from postzygotic somatic mosaicism or 47,XXY (Klinefelter syndrome)
  • Phenotypic variability reflects random X-inactivation (functional mosaicism) and postzygotic mosaicism; no genotype-phenotype correlation established
  • Point and small mutations predominate in sporadic cases, larger deletions in familial cases; germline mosaicism reported
  • Blood DNA testing may be negative in mosaic patients; testing DNA from affected skin or fibroblasts improves diagnostic yield

References